Lena M. Napolitano, MD, FCCM
University of Michigan School of Medicine
Ann Arbor, Michigan, USA


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References

Anemia in Critical Care: Prevalence, Pathophysiology, and Prevention

Prevention of anemia is crucial, as it is the most common indication for blood transfusion in the intensive care unit (ICU). Anemia is a common problem in critically ill patients; the causes are multifactorial and include blood loss from multiple sources and suppressed erythropoiesis.

Prevalence of Anemia and Blood Transfusion in Critical Care
Anemia is pervasive in the ICU. Red blood cell (RBC) transfusions are commonly used to treat anemia in critical care, resulting in a high use of a scarce resource. A number of recent large prospective studies have examined the prevalence of anemia and use of blood transfusion in the ICU. The Anemia and Blood Transfusion in Critical Care (ABC) trial,1 a prospective observational study conducted in Western Europe, examined the incidence of anemia and the use of RBC transfusions in critically ill patients. The study included 3,534 patients from 146 Western European ICUs. The mean hemoglobin level at ICU admission was 11.3 g/dL, with 29% of patients having a level of less than 10 g/dL. The ICU transfusion rate for the entire cohort was 37%. Patients admitted for emergency surgery were transfused at the highest rate (57.5%), followed by those admitted for trauma (48.0%), elective surgery (42.1%), and medical reasons (32.0%).

Older patients and those with a longer ICU length of stay were transfused more often. Of patients with an ICU length of stay of more than seven days, 73% received a blood transfusion. The overall mean pre-transfusion hemoglobin level was 8.4 g/dL in this study. A similar prospective, multicenter, observational, cohort study in the United States, the CRIT Study, enrolled 4,892 patients from 284 ICUs.2 Mean baseline hemoglobin level on admission to the ICU was 11.0 g/dL, which significantly decreased to 9.8 g/dL by the end of study. Forty-four percent of patients were transfused (mean 4.6 units) during their ICU stay. Patients with an ICU length of stay of seven days or more were transfused more commonly (63%) than those with a shorter stay (33.4%). Mean pretransfusion hemoglobin was 8.6 g/dL in this study.

A prospective cohort study from the Transfusion Requirements in Critical Care (TRICC) investigators and the Canadian Critical Care Trials Group examined 5,298 consecutive ICU patients and documented that 25% received RBC transfusion. The overall number of transfusions per patient-day in the ICU averaged 0.95.3 Another prospective observational study assessed the current transfusion practice in ICU patients in the United Kingdom4 and determined that 666 of 1,247 (53%) consecutive ICU patients received RBC transfusions. The average pre-transfusion hemoglobin level was <9 g/dL in 75% of transfusion episodes. The common indications for transfusion were anemia (72%) and hemorrhage (25%). The Audit of Transfusion in Intensive Care in Scotland (ATICS) study examined ICU transfusion practices in patients with or without ischemic cardiac disease.5 Overall 39.5% of patients received RBC transfusion. Pretransfusion hemoglobin levels ranged from 7.4 g/dL in patients without ischemic cardiac disease to 7.7 and 7.9 g/dL in patients with documented ischemic cardiac disease and a non-cardiac versus cardiac ICU admission diagnosis, respectively.

The epidemiologic studies examining anemia in the ICU (see Table 1) reveal a number of similarities. First, the majority of ICU patients have anemia on admission. Second, the transfusion trigger (i.e., pre-transfusion hemoglobin level) in most studies was hemoglobin level of approximately 8.5 g/dL. Third, RBC transfusion rates were increased in patients with a prolonged length of stay in the ICU and more advanced age. Finally, the most common indication for RBC transfusion in the ICU was the treatment of anemia.

Anemia and Transfusion in Trauma, Burns, and Sepsis
Increased transfusion rates have been reported in trauma, burn, and sepsis patients. A post hoc analysis of the subset of trauma patients (n =576) from the CRIT Study documented a higher transfusion rate in critically ill trauma patients.6 Mean (+ SD) baseline hemoglobin measurement was 11.1 ± 2.4 g/dL, and patients remained anemic throughout the study with or without transfusion; 55.4% of patients were transfused (mean, 5.8 ± 5.5 units) during the ICU stay, and 43.8% of patients had an ICU length of stay of seven days or longer. The mean pre-transfusion hemoglobin level was 8.9 ± 1.8 g/dL. When compared with the full ICU study population, patients in the trauma subset were more likely to be transfused (55.4% vs. 44%) and received an average of one additional unit of blood. This study confirmed that anemia is common in critically injured trauma patients and persists throughout the duration of critical illness, resulting in a large number of RBC transfusions. A multicenter retrospective cohort analysis of blood transfusion practices in burn patients (n = 666) documented that 74.7% of patients received blood during their hospital stay, with a total of 8,488 units of blood transfused.7 The mean total number of blood transfusions per patient throughout the hospital stay was 13.7 ± 1.1 units, with 4.3 ± 0.3 units transfused in the operating room. Pre-transfusion hemoglobin levels ranged from 8.9 to 10.2 g/dL.

Trauma and burn patients are more likely to be transfused, are transfused at a higher hemoglobin level, and receive more RBC units than other critically ill patients. Similarly, septic patients are at higher risk for anemia. The time course of hemoglobin levels in non-bleeding ICU patients (n = 91) was examined in a prospective, single-institution observational study in a medical-surgical ICU.8 These patients had no evidence of recent or active blood loss, no history of hematologic disease or chronic renal failure, and no need for renal replacement therapy.

Hemoglobin levels still declined by >0.5 g/dL per day during the first days of the ICU stay in these non-bleeding patients. Beyond the third ICU day, hemoglobin levels remained relatively constant in non-septic patients but continued to decrease in septic patients.

Anemia on ICU Discharge
Anemia is present in a high proportion of critically ill patients at ICU discharge and may impact functional recovery negatively. The ATICS study documented that 25% of patients had a hemoglobin level <9 g/dL at ICU admission. Interestingly, the prevalence of anemia was significantly higher, present in approximately 80% of patients, at ICU discharge.9 This study clearly documented that a restrictive transfusion practice in the ICU is associated with a high prevalence of anemia at ICU discharge.

Furthermore, risk factors for post-ICU RBC transfusion were identified in a recent prospective study and included sepsis, underlying medical conditions, unresolved organ failure, and low hemoglobin level at discharge. Anemia may impair the ability to recover functionally after hospital discharge. Elderly patients with hemoglobin levels below 12 g/dL at discharge had a higher rate of failure to achieve independence in activities of daily living (7.0% vs. 11.6%).10 Strategies to prevent transfusion must take into account the post-ICU needs for RBC transfusion.11

Etiology of Anemia in Critical Illness
Anemia in critical illness is multifactorial. Contributing etiologies include hemodilution and blood loss related to phlebotomy for diagnostic testing, occult gastrointestinal bleeding, renal replacement therapies, surgical intervention, and traumatic injuries. However, the inflammatory state of critically ill patients is the underlying mechanism behind what is referred to as anemia of inflammation or anemia of critical illness.

The clinical manifestations of this anemia include depressed serum iron levels despite adequate reticuloendothelial iron stores, decreased total iron-binding capacity, and increased serum ferritin. Intestinal iron absorption is impaired. Hepcidin, a peptide produced by hepatocytes in response to interleukin-6 as part of the acute phase response, is a pivotal regulator of iron metabolism. Hepcidin is induced markedly during infections and inflammation and promotes the retention of iron in macrophages, hepatocytes, and enterocytes by inhibiting the efflux of iron through ferroportin. The resulting decrease in plasma iron levels eventually limits iron availability to erythropoiesis and contributes to the anemia of inflammation. Interestingly, this hepcidin-induced decrease in extracellular iron stores also probably limits iron availability to invading microorganisms, thus contributing to host defense.12

Reduced red cell life span and nutritional deficiencies (iron, folate, vitamin B12) may be other contributing factors. Iron deficiency has been identified in 9% of ICU patients and folate or B12 deficiency in 4% of ICU patients.13 In addition, critically ill patients have impaired erythropoiesis because of blunted endogenous erythropoietin production and the direct inhibitory effects of inflammatory cytokines on red blood cell production by the bone marrow (see Figure 1).

Predicting Anemia in Critical Care

The early identification of patients at risk for anemia in the ICU potentially could permit earlier intervention and the institution of blood transfusion-sparing or anemia management strategies. The recent development of an ICU anemia score, using information available within six hours of ICU admission, enabled healthcare professionals to predict the likelihood of late anemia with reasonable accuracy.14 This will require validation in other studies before routine application in clinical care. Early identification of anemia is important when considering initiation of erythropoiesis-stimulating therapies that require a long lead time before an effect is seen.

Preventive Strategies for Anemia in the ICU

Efforts to conserve blood and adherence to transfusion guidelines could reduce RBC transfusion significantly in the ICU. Phlebotomy for diagnostic laboratory testing contributes to blood loss in ICU patients. A prospective study examined phlebotomy volume in 96 medical ICU patients with ICU lengths of stay longer than three days.15

Diagnostic blood loss declined from a median of 41 mL on day one to <20 mL after three weeks and contributed 17% (median) to total blood loss. Acute renal failure, fatal outcome, and a simplified acute physiology score >38 on admission were associated with a 5.8-, 7.0-, and 2.8-fold increase in total blood loss, respectively. In the ABC trial,1 a prospective, observational blood sampling study also was conducted. The mean volume per blood draw was 10.3 ± 6.6 mL, with an average total volume of 41.1 ± 39.7 mL during the 24-hour period. There was a positive correlation between organ dysfunction and the number of blood draws (r =.34; p < 0.001) and total volume drawn (r = 0.28; p < 0.001). Similarly, Nguyen et al also documented that the volume of blood drawn daily for laboratory studies was 40.3 ± 15.4 mL (49.0 ± 11.3 mL in septic patients vs. 36.7 ± 14.9 mL in non-septic patients, p = 0.04).8

The use of a blood conservation device to minimize diagnostic phlebotomy blood loss in critically ill patients has been documented to be efficacious. A prospective, randomized, controlled trial in 100 medical ICU patients confirmed that a device incorporated into the arterial pressure monitoring system resulted in significant blood conservation.16 The volume of blood drawn and discarded from arterial catheters was significantly lower in the blood conservation group (blood conservation device: 5.7 ± 7.5 mL; control: 96.4 ± 88.5 mL; p < 0.0001), as was the total volume of blood discarded (blood conservation device: 19.4 ± 47.4 mL; control: 103.5 ± 99.9 mL; p < 0.0001).

Univariate and multiple regression analysis demonstrated discarded blood volume to be a significant and independent predictor of the decline in hemoglobin level, a result validated in other studies.17 A recent survey of arterial blood sampling practices in 280 ICUs throughout England and Wales found that few measures were taken to reduce diagnostic blood loss from arterial sampling in adult patients.18 The average volume of blood withdrawn to clear the arterial line before sampling was 3.2 mL, which subsequently was returned to the patient in only 18.4% of ICUs. Specific measures to
reduce the blood sample size by the routine use of pediatric sample tubes in adult patients occurred in only 9.3% of ICUs. In pediatric ICUs, the average volume withdrawn was 1.9 mL, which routinely was returned in 67% of units. The practices identified in this survey contribute to iatrogenic anemia in ICU patients.

Most recently, a survey of Australian ICUs documented that only 16% of units return dead space blood volumes from in-line arterial sets, and no ICU routinely used pediatric blood collection tubes. Using a highly conservative phlebotomy protocol, median phlebotomy-associated blood loss was reduced by more than 80% (40 mL vs. 8 mL, p < 0.001).19

Neonatal and pediatric critical care have embraced these practices, and recent studies have documented a significant reduction in RBC transfusion by the use of a point-of-care
technology, including a novel bedside laboratory monitor that returned analyzed blood to the patient.20,21

Conclusion

More study is needed to understand further the pathophysiology of ICU-acquired anemia, and to elucidate risks and benefits of RBC transfusion and the pharmacologic augmentation of erythropoiesis in critical care. We also must investigate alternatives to blood transfusion for the treatment of anemia in the ICU, but at present we should focus on prevention. Strategies to reduce blood loss related to diagnostic phlebotomy, including use of pediatric tubes, low-volume adult tubes, point-of-care testing, and blood conservation devices, should be implemented in all ICUs. These simple preventive strategies can have a significant effect on reducing the incidence of anemia in ICUs and reducing the need for allogeneic blood transfusion in critical care.